The Developmental Genetics Laboratory
In the last few years the discovery of histone acetyltransferases has revolutionised research into the regulation of gene expression and how the genome is organised. Current models propose that the transcription machinery used for protein coding genes requires co-activator complexes to link DNA binding transcription factors to the basal transcriptional apparatus. Co-activator complexes are potent regulators of current and future patterns of gene expression and therefore directly control proliferation and lineage determination. Not surprisingly de-regulation of these molecules lead to diseases such as leukaemia.
Co-activator complexes typically contain proteins that regulate the organization of chromatin by covalent modification of histones. One of the most important types of modification is the addition of acetyl groups to lysine residues in the N-terminal tail of histones. This is catalysed by histone acetyltransferases and co-activator complexes typically contain one or more of these enzymes. This shows that modification of chromatin structure is an essential aspect of the regulation of gene expression.
A simplified model of how histone acetylation mediated by Myst family transferases may act to regulate gene expression (A). Acetylation can occur on the lysine residues within the N-terminal "tail" of histones, as shown for histone 3 and histone 4 (B). The structural relationship between different MYST family members (C).
Since the ability to dramatically change gene expression patterns upon receiving external signals is the key property of stem cells, it follows that in order to understand the biology of stem cells it is necessary to identify the important co-activators in these cells and define their function.
Cells of the early embryo lacking the MYST histone acetyltransferase Mof show reduced levels of acetylation on histone 4 lysine 16, which results in abnormally condensed chromatin (compare D and E with A and B). Note that in the mutant cells there are reduced levels of histone 3 lysine 14 acetylation, a marker of transcriptionally active chromatin (F vs. C). Figure from Thomas et al. MCB 2008.
Our aim is to define the role of co-activators of transcription in stem and progenitors cells during embryonic development and in adults. We are particularly interested in the function of the MYST family of histone acetyltransferases in stem cell populations. We have shown that Moz is essential for the development of haematopoietic stem cells whereas Qkf has an essential role in adult neural stem cells. We are currently investigating the function of the MYST family, particularly Moz and Qkf, during embryonic development and in adult stem cell populations.